Disulfiram (Antabuse) is an important component of many alcoholism treatment programs. One of the reasons it is not used more widely is its neurotoxicity. Chronic administration of disulfiram may produce both peripheral and central nervous system impairment ranging from sensory and motor deficits to cognitive difficulties. Among the mechanisms proposed to account for these neurotoxic reactions is the ability of disulfiram to chelate metals. Disulfiram belongs to a chemical class known as dithiocarbamates whose members are also used in agriculture, industry, and cosmetics. In medicine, they may be used specifically as chelating agents to reduce toxic levels of certain metals. Considerable data indicate that dithiocarbamate-metal complexes, however, penetrate more easily into the brain, probably because of their lipophilic properties, and may greatly enhance metal levels in brain tissue at the same time that they may reduce kidney concentrations, for example. The functional consequences of this action remain to be determined. This proposal outlines the preliminary steps of a project whose aim is to do so. One step is to measure the brain levels of methylmercury (a recognized neurotoxicant) and cadmium (at best, a weak neurotoxicant) in rats also treated with disulfiram. This part of the project is basically a dose-ranging study. Another step is to devise a suitable method for assessing the kind of neurotoxic responses that might arise with such treatment. The technique proposed relies on schedule-controlled behavior coupled with a response, wheel-running, that also reflects the capacity for coordinated movement. The eventual outcome of this research will help clarify the contribution of metal toxicity to disulfiram toxicity, and enlarge our understanding about the joint risk of disulfiram treatment and toxic metal exposure.